A lower CD4 count before starting antiretroviral therapy (ART) raised chances of a greater loss in bone mineral density (BMD) after 96 weeks of treatment, according to an analysis of 796 people enrolled in three AIDS Clinical Trials Group (ACTG) studies [1]. The finding confirms previous research and supports the hypothesis that pretreatment CD4 status and CD4 recovery with ART affect BMD during treatment.

Research shows that BMD declines from 2% to 6% in the first years of ART then usually stabilizes. Reasons for this drop remain unclear. Nor is it entirely clear whether falling BMD after ART begins holds true regardless of pretreatment CD4 count, although some studies cited below indicate such an association. To address these issues, ACTG investigators pooled data from three trials that enrolled people starting their first regimen. These trials, ACTG A5005s, A5142, and A5224s, enrolled people in 1998-1999, 2003-2004, and 2005-2007 and compared regimens incorporating efavirenz, nelfinavir, lopinavir/ritonavir, atazanavir/ritonavir, tenofovir, and array of nucleosides.

The researchers performed multivariate linear regression analyses to examine associations between BMD change after 96 weeks of treatment, pretreatment CD4 count, and absolute and relative 16-week change in CD4 count. They looked specifically at the potential impact of regimens containing tenofovir or protease inhibitors while considering numerous demographic and clinical variables (not including smoking).

The analysis included 796 people, 93 from ACTG A5005s, 503 from A5142, and 200 from A5224s. Median ages in A5005s, A5142, and A5224s were 37, 38, and 40, proportions of men were 88%, 82%, and 85%, and proportions of blacks were 30%, 39%, and 30%. Median initial body mass index was consistent across the three studies--24, 25, and 25 kg/m(2). Median pretreatment CD4 counts were 265 in A5005, 184 in A5142, and 255 in A5224.

Numbers of study participants by pretreatment CD4 count were 168 below 50, 215 at 50 to 199, 246 at 200 to 349, 114 at 350 to 499, and 52 at 500 or more. Average change in 96-week BMD approached -5% in people who started treatment with fewer than 50 CD4s and rose in stepwise fashion to almost no change in people who started with at least 500 CD4s (P < 0.001, see Figure 1 in poster linked below). BMD decline through 96 weeks was significantly greater in people who took tenofovir than in those who did not (P < 0.001) and significantly greater in those who took a protease inhibitor than in those who did not (P = 0.017) (see Figure 2 in poster linked below).

Every 10-fold higher pretreatment viral load was associated with an average 96-week BMD change of -0.56 (95% CI -0.92 to -0.20, P = 0.002). Starting a tenofovir regimen was associated with an estimated average change in BMD of -1.38 (95% CI -1.90 to -0.87, P < 0.001), and starting a protease inhibitor regimen was associated with a change of -0.80 (95% CI -1.27 to -0.33, P = 0.001).

Every 1 kg/m(2) higher pretreatment body mass index was linked to a significantly greater week-96 estimated average change in BMD (+0.10, 95% CI +0.06 to +0.15, P < 0.0010). Compared with women, men had a significantly greater change in 96-week estimated average change in BMD (+0.84, 95% CI +0.24 to +1.45, P = 0.007). Every additional year of age was associated with a significantly lower 96-week average BMD change (-0.05, 95% CI -0.07 to -0.02, P < 0.001).

The ACTG team concluded that lower pretreatment CD4 count is "a strong and independent risk factor for bone loss after ART initiation." They proposed that starting antiretroviral therapy at a higher CD4 count "may reduce the burden of osteoporosis and fragility fracture among HIV-infected patients."

Lower nadir CD4 count predicted low BMD in a previous analysis of ACTG A5224s [2] and
among men (but not women) in the 892-person French FOSIVIR trial of [3]. But lower nadir CD4s did not emerge as an independent predictor of low BMD in a national Brazilian study of 300 people with HIV [4]. An Australian case-control study linked an on-treatment CD4 count below 200 (as well as corticosteroids and antiepileptics) with a higher risk of fragility fractures [5]. Groups in France and the United States reported an association between nadir CD4 count and development of osteoporosis or osteopenia [6,7].